Aqueous perfluorocarbon emulsions have been explored as blood substitutes, especially for transfusions. One goal in such formulations has been to employ a perfluorocarbon of greatest oxygen solubility to the maximum concentration feasible while maintaining a perflurocarbon-in-water emulsion. Emulsifiers (surfactants) for such applications are reviewed in I.R. Schmolka, "Artificial Blood Emulsifiers," Federation Proceedings, vol. 34, pp. 1449-1453 (1975). There, various desired properties of the non-ionic emulsifiers are set forth, including non-toxicity. The paper also discusses the distinctions between a microemulsion and a macroemulsion (droplet size under 0.1 microns versus 0.1 to 2 microns). The paper indicates that when two surfactants are used, then rather than mixing the two together, one should dissolve the water-soluble surfactant in the aqueous phase and the water-insoluble surfactant in the oil (perfluorocarbon) phase. A similar teaching is contained in U.S. Pat. No. 4,146,499 to Rosano (1979), which emphasizes mixing order (the water-insoluble surfactant and then the water-soluble surfactant) and discounts as incorrect the pre-1972 belief that microemulsions should be thought of as thermodynamically stable systems. It is reasonable to infer from Rosano that his clear microemulsions are metastable rather than thermodynamically stable, being dependent for their formation upon adding ingredients in a particular order (creating a specified "transient" condition). When such metastable microemulsions are broken (generally by heating too hot or freezing), they would not reform upon returning to room temperature, even with mild agitation. In some cases, no amount of agitation can restore such metastable emulsions once broken.
Perfluorocarbon-in-water emulsions have been disclosed for use as blood gas controls and calibrators. See U.S. Pat. Nos. 4,151,108 and 4,163,734 to Sorenson and U.S. Pat. Nos. 4,299,728 and 4,369,127 to Cormier et al. In such cases, the aqueous phase is buffered for an assayable pH value and is equilibrated with oxygen-containing gases for an assayable pO.sub.2 value. A blood gas control also has an assayable pCO.sub.2 value which is obtained by one or more of:
(a) equilibration with CO.sub.2 -containing gases, PA0 (b) addition of a bicarbonate source, and PA0 (c) addition of a carbonate source (some pH adjustment being sometimes employed for some of these, e.g., NaOH added when CO.sub.2 -containing gases are the sole manner of introducing CO.sub.2).
The fluorocarbon is chosen as one with high oxygen solubility so that the overall emulsion will dissolve more oxygen at a given temperature than water does (leading to an "oxygen-buffering" effect in that the pO.sub.2 value is deflected less from the assayed value under circumstances such as brief contact with air). FC-77 and FC-43 are used in admixture in the Cormier et al patents.
Commercial blood gas controls, including those based upon the Cormier et al patents, are macroemulsions that are stable (against breaking) for extended periods (at least two years, but not indefinitely), but have a tendancy within a few days to cream, i.e., form a layer enriched in the discontinuous fluorocarbon phase (analogous to the creaming of the discontinuous oily phase in non-homogenized milk but tending to sediment since the fluorocarbon phase is denser than the aqueous phase). The creamed composition can be restored by manual shaking. If, however, the macroemulsions are broken (e.g., because of temperature either much higher or lower than the desired range), they cannot be restored except by vigorous agitation (as by reintroduction of the mixture into a homogenizer) which cannot be accomplished easily for sealed ampules of a blood gas control having assayed values which are desired to be maintained.